Main Outcome Measures Episodes of febrile illness, severe febrile illness, febrile upper respiratory
tract illness, work loss, and health care use during the peak and total influenza
outbreak periods, and adverse events.

Results Recipients of LAIV vaccine were as likely to experience 1 or more febrile
illnesses as placebo recipients during peak outbreak periods (13.2% for vaccine
vs 14.6% for placebo; P=.19). However, vaccination
significantly reduced the numbers of severe febrile illnesses (18.8% reduction;
95% confidence interval [CI], 7.4%-28.8%) and febrile upper respiratory tract
illnesses (23.6% reduction; 95% CI, 12.7%-33.2%). Vaccination also led to
fewer days of illness across all illness syndromes (22.9% reduction for febrile
illnesses; 27.3% reduction for severe febrile illnesses), fewer days of work
lost (17.9% reduction for severe febrile illnesses; 28.4% reduction for febrile
upper respiratory tract illnesses), and fewer days with health care provider
visits (24.8% reduction for severe febrile illnesses; 40.9% reduction for
febrile upper respiratory tract illnesses). Use of prescription antibiotics
and over-the-counter medications was also reduced across all illness syndromes.
Vaccine recipients were more likely to experience runny nose or sore throat
during the first 7 days after vaccination, but serious adverse events between
the groups were not significantly different. The match between the type A(H3N2)
vaccine strain and the predominant circulating virus strain (A/Sydney/05/97[H3N2])
for the 1997-1998 season was poor, suggesting that LAIV provided substantial
cross-protection against this variant influenza A virus strain.

Conclusion Intranasal trivalent LAIV vaccine was safe and effective in healthy,
working adults in a year in which a drifted influenza A virus predominated.

Figures in this Article

Influenza type A and B viruses cause illness in 10% to 20% of the population
each year.1 Prominent manifestations of illness
include decreased ability to perform daily activities and increased health
care resource use. Among working adults, influenza accounts for millions of
work-loss days and physician office visits each year.2,3
Although healthy, working adults are not currently targeted for routine annual
vaccination,4 immunization with inactivated
influenza virus vaccines can be associated with substantial health and economic
benefits for this group.5

Live, attenuated influenza virus (LAIV) vaccines offer a new option
for the prevention and control of influenza. These vaccines do not require
an injection for administration and because intranasal administration results
in infection with the attenuated virus strains, they may more effectively
stimulate mucosal and cell-mediated immune responses.1,6- 9
Among children, monovalent and bivalent vaccines are at least as efficacious
as inactivated influenza virus vaccines.10,11
In a recent placebo-controlled trial among children aged 15 to 71 months,
intranasally administered trivalent LAIV vaccine reduced culture-confirmed
influenza infection by 93%.12 Studies using
primarily monovalent or bivalent formulations have shown that these vaccines
are safe, immunogenic, and efficacious among healthy adults as well.1,6,13- 16
Trivalent LAIV vaccine has reduced experimentally induced influenza in adult
volunteers by 85%.17 A 5-year study of bivalent
LAIV vaccine demonstrated protection against natural influenza A infection
among children and adults that was approximately equivalent to that of trivalent
inactivated vaccine.18 The present study assesses
the safety and effectiveness of trivalent LAIV vaccine among healthy adults
for reducing clinical illness, absenteeism, and health care use.

METHODS

Design and Subjects

This study was a randomized, double-blind, placebo-controlled trial.
Participants were enrolled from 13 sites across the continental United States
between mid-September and mid-November 1997. Recruitment strategies differed
by site and included recruitment through specific health insurance carriers
and work sites as well as from the general population, using a variety of
advertising media. Persons were eligible if they were 18 to 64 years old,
they worked at least 30 h/wk outside of the home, they had health insurance,
and they were available for follow-up telephone calls. Exclusion criteria
included a history of acute hypersensitivity to eggs or egg products, previous
receipt of the 1997-1998 inactivated influenza vaccine, self-reported pregnancy
or unprotected risk for pregnancy within the previous 3 months, and acute
febrile illness or upper respiratory tract illness within 72 hours. Because
of the placebo-control arm of the study, exclusion criteria also included
the presence of any indications for routine vaccination with the inactivated
vaccine, such as the presence of high-risk medical conditions or positions
of employment that involve significant contact with high-risk people. Study
participants received up to $100 as a financial incentive. The study was approved
by the institutional review board at each site and written informed consent
was obtained from all participants.

Vaccine

The LAIV vaccine for the 1997-1998 season (FluMist, Aviron) included
3 live, attenuated influenza virus strains: A/Shenzhen/227/95 (H1N1), A/Wuhan/359/95
(H3N2), and B/Harbin/7/94-like, in egg allantoic fluid containing sucrose-phosphate-glutamate
(SPG). These strains were antigenically equivalent to those included in the
inactivated vaccine for the 1997-1998 season.19
The placebo, which consisted of egg allantoic fluid containing SPG, was indistinguishable
in appearance and smell from the vaccine. Vaccine and placebo were supplied
in single-dose intranasal sprayers. Participants were provided with instructions
on intranasal administration of the vaccine and were given the option of self-administration
under direct supervision of or administration by a study staff member. To
allow sufficient time for an immune response to develop before any anticipated
influenza outbreaks, vaccine or placebo was administered between September
18 and November 15, 1997.

Randomization and Masking

Participants were randomized 2:1 to receive the investigational LAIV
vaccine or placebo. To ensure balanced allocation of subjects between vaccine
and placebo within each site, randomization was performed using 6-unit blocks.
Participants were randomized at the time of vaccination. Each new participant
was assigned to the next available sequential allocation number according
to the predetermined, computer-generated randomization schedule. The sequential
number imprinted on the vaccine label determined the material used for vaccination.
Adherence to the predetermined allocation sequence was documented through
accountability logs. Both the vaccine and placebo were prelabeled according
to the computer-generated randomization schedule provided by Statistics Collaborative,
Washington, DC, packaged to be visually identical, and delivered to the study
sites by Almedica Service Corp, Waldwich, NJ. Blinding to intervention assignment
of the study participants and site personnel was maintained until all outcome
data had been collected and verified.

Data Collection

Baseline Data and Safety and Tolerability of Vaccine.

Information on participant demographic characteristics, medical history,
and current use of medications was collected at the time of enrollment. For
assessment of postvaccination reactogenicity symptoms and other adverse events,
participants were given a reactogenicity symptom card and a digital thermometer
and were instructed to record daily temperatures and check off the presence
of respiratory tract symptoms (cough, sore throat, and runny nose) and other
systemic symptoms (headache, chills, muscle aches, and tiredness or weakness)
on a daily symptom checklist beginning on the evening of vaccination and daily
thereafter for 7 days. They were also asked to list other symptoms and any
medications used during the week following vaccination. Study personnel telephoned
participants 7 days after vaccination to remind them to return the reactogenicity
cards. Participants were also called 28 days after vaccination to identify
the occurrence of any serious adverse events during the 28 days following
vaccination that had not been reported on the reactogenicity cards. Assessment
and recording of any additionally reported serious adverse events continued
through the end of the study.

Illness Episodes, Health Care Use, and Work Loss.

To assess occurrences of illness, health care use, and work loss for
each month from November 1997 through March 1998, participants completed symptom
and illness cards on which they daily checked off symptoms present, including
self-reported fever, respiratory tract symptoms (cough, sore throat, and runny
nose) and other systemic symptoms (headache, chills, muscle aches, and tiredness
or weakness). They also recorded whether they missed work, visited a health
care provider, took antibiotics, and used over-the-counter medications for
illness symptoms. A computer-generated telephone messaging system reminded
participants to complete and return the cards.20

Regional Influenza Surveillance.

For each recruitment site, a laboratory was identified that conducts
influenza viral surveillance in the geographic area from which participants
were recruited. These laboratories were contacted weekly from November 1997
through March 1998 for reports on the number of specimens submitted for influenza
testing, the number of specimens with positive results, and strain identification,
if performed. This information was supplemented by surveillance data from
the Centers for Disease Control and Prevention, Atlanta, Ga. The combined
data were used to define 2 influenza outbreak periods: site-specific peak
outbreak periods and total outbreak periods. Site-specific
peak outbreak periods were defined using a prespecified algorithm that
began with the modal week for positive influenza isolates in the community
around each study site and sequentially included weeks both before and after
the peak week for which there were positive isolates until at least 80% of
isolates for the season were included. Thetotal outbreak
period was defined by an expert panel blinded to study outcomes after
inspection of histograms showing the numbers of positive isolates by week
for all sites combined. During site-specific peak outbreak periods, it was
expected that the clinically defined illness syndromes would have a greater
degree of specificity for true influenza illness and would therefore provide
a more precise estimate of vaccine effectiveness. The total outbreak period,
on the other hand, was expected to provide a broader overall assessment of
the impact of influenza and its prevention on the study population.

Illness Definitions

The primary effectiveness end point for the study was the proportion
of participants reporting 1 or more febrile illnesses
during the peak outbreak periods. Subjects were characterized as having a
febrile illness if they had symptoms for at least 2 consecutive days, with
fever on at least 1 day, and if they had 2 or more symptoms (fever, chills,
headache, runny nose, sore throat, cough, muscle aches, tiredness/weakness)
on at least 1 day. This illness category was expected to be quite sensitive
but not very specific for true influenza illness. Two additional prespecified
febrile illness syndromes that were expected to correlate with more severe
illness and/or to have a higher degree of specificity for true influenza illness
were examined. These included severe febrile illness
(at least 3 consecutive days of symptoms, at least 1 day of fever, and 2 or
more symptoms on at least 3 days) and febrile upper respiratory
tract illness (at least 2 consecutive days of upper respiratory tract
symptoms [runny nose, sore throat, or cough], fever on at least 1 day, and
2 symptoms on at least 1 day).

Analysis

All randomized participants were included in the analyses if they provided
any safety and tolerability or clinical effectiveness data. Participants for
whom no follow-up data were available were excluded from the analyses. Bivariate
comparisons for the proportions of subjects experiencing study outcomes were
conducted using the Cochran-Mantel-Haenszel test, controlling for site. Because
the end points that measured counts such as the numbers of illness episodes
were distributed approximately according to the Poisson distribution, we used
generalized linear models to calculate the variance of the event rates to
allow for hypothesis testing (PROC GENMOD, SAS, Version 6.12, SAS Institute
Inc, Cary, NC). Outcome rates were adjusted for the duration of follow-up
data available for each subject and the duration of the site-specific peak
outbreak periods, when appropriate. For assessing the rates of adverse effects
during the 7 days following vaccination, clinical equivalence was defined
as occurring if the upper limit of a 2-sided 95% confidence interval (CI)
for the difference in rates was no more than 5% for fever and no more than
10% for the other reactogenicity symptoms.

The sample size estimates for the trial were based on achieving 90%
power for the primary effectiveness end point. At least 4200 participants
would be required to have 90% power to detect a difference of 2.52%, assuming
that 6% of placebo recipients would experience a febrile illness, 70% of these
illnesses would be due to influenza, vaccine efficacy would be 60%, 3.48%
of vaccine recipients would experience febrile illness, and outcome data would
be available for 80% of participants. This sample size also afforded 99% power
to demonstrate similar reactogenicity rates between vaccine and placebo recipients
using the equivalence definitions provided herein.

RESULTS

A total of 4561 persons were randomized from September 18 through November
15, 1997 (Figure 1). The demographic
characteristics of the 3041 vaccine recipients and 1520 placebo recipients
were well balanced between the groups (
Table 1).

Figure 1. Trial Profile

During the days 0-28 safety phase of the trial, 3 participants (2
in vaccine group [0.07%] and 1 in placebo group [0.07%]) withdrew because
of adverse events. The 2 events among vaccine recipients were a hospitalization
for Crohn disease and an accidental drowning complicated by acute alcohol
intoxication. The event in a placebo recipient was related to psychiatric
illness not requiring hospitalization. None of these events was judged to
be related to receipt of the study treatment by the blinded study investigators.
An additional 15 participants (10 in vaccine group [0.3%] and 5 in placebo
group [0.3%]) either withdrew voluntarily or were noncompliant. Sixty-nine
vaccine recipients (2.3%) and 31 placebo recipients (2.0%) were lost to follow-up
and 2 others (1 in each group) cited other reasons for not providing the day
28 safety data. During the clinical effectiveness phase of the trial, participants
who did not return the symptom cards were considered lost to follow-up. LAIV
indicates live attenuated influenza virus.

Adverse Effects

Seventy-one percent of vaccine recipients and 69% of placebo recipients
self administered the vaccine or placebo. In both groups, 96% of persons self
administering did so without difficulty. Reactogenicity data for the 7 days
following vaccination were available for 98.2% of vaccine recipients and 98.0%
of placebo recipients. Vaccine recipients were more likely than placebo recipients
to experience a runny nose (44.3% vs 26.6%; difference, 17.7%; 95% CI for
difference, 14.7%-20.7%) during the week following vaccination. Among persons
with a runny nose, the duration was similar between the groups (median duration,
2 days for both groups; 25th percentile, 1 day for both groups; 75th percentile,
4 days for vaccine group and 5 days for placebo group). Vaccine recipients
were also more likely to report a sore throat (26.6% vs 16.3%; difference,
10.3%; 95% CI for difference, 7.7%-12.9%) during the week following vaccination.
As with runny nose, the duration of sore throat symptoms was similar between
the 2 groups (median duration, 2 days for both groups; 25th percentile, 1
day for both groups; 75th percentile, 3 days for both groups). Neither symptom
resulted in increased use of antibiotics, analgesics/antipyretics, or decongestants/antihistamines/antitussives
among vaccine recipients. The 2 groups had equivalent rates of other symptoms
during the 7 days following vaccination (
Figure 2).

Figure 2. Proportion of Study Participants
Reporting 1 or More Days of Symptoms During the 7 Days Following Vaccination

Asterisks indicate symptoms for which the rate among vaccine recipients
was significantly higher than among placebo recipients, with the upper limits
of the 95% confidence intervals for the differences including or exceeding
10% (see "Methods" section of text). The rates of the other symptoms were
equivalent between the groups. Fever was defined as an oral temperature of
more than 37.8°C.

During the 28 days following vaccination, 9 serious adverse events were
reported: 5 among vaccine recipients (0.18%) and 4 among placebo recipients
(0.27%; P=.50). These included 8 hospitalizations
(4 in each group) and 1 death (vaccine group) due to an accidental drowning
complicated by alcohol intoxication. None was judged by blinded study investigators
to be related to the study treatment. An additional 49 serious adverse events
were reported during the clinical effectiveness outcome periods, including
30 (1.0%) among vaccine recipients and 19 (1.3%; P=.50)
among placebo recipients. Each represented a hospitalization judged by the
blinded investigators not to be related to receipt of the study treatment.

Outbreak Isolates

The peak outbreak periods lasted from 4 to 12 weeks at the different
sites, with a median duration of 7 weeks. The total outbreak period for all
study sites combined extended from December 14, 1997, through March 21, 1998.
This 14-week period was similar to that seen nationally for the 1997-1998
influenza season (Figure 3). More
than 99% of influenza isolates from the study site laboratories were type
A, and more than 99% of the subtyped isolates were A(H3N2) viruses. This predominance
was also similar to what was seen throughout the United States for that season.21,22 Nationally, 80% of the further subtyped
A(H3N2) viruses were A/Sydney/5/97-like, a drifted variant from the A(H3N2)
component included in the vaccine.21,22

Figure 3. Weekly Influenza Surveillance for
the 1997-1998 Influenza Season

Shown on the y-1 axis, with the bars, are the numbers of positive
influenza type A isolates reported to the Centers for Disease Control and
Prevention, Atlanta, Ga, by the World Health Organization collaborating laboratories
in the United States (adapted from reference 22). Shown on the y-2 axis, with
the line, are the numbers of positive influenza A isolates reported by the
study site laboratories. Fewer than 1% of all influenza isolates during the
1997-1998 season were influenza type B isolates and were therefore omitted
from the graph.

Outcomes

Vaccine recipients returned 10,869 (89.4%) of 12,164 symptom cards for
the 4-month, 14-week pooled outcome period, while placebo recipients returned
5451 (89.7%) of 6080 cards. During the 14-week total outbreak period, 94.4%
of participants returned at least 1 card, while 93.2% returned at least 1
card during the peak outbreak period. Fewer vaccine recipients (373/2833)
experienced 1 or more febrile illnesses than did placebo recipients (207/1420)
during the peak outbreak period, although this difference did not reach statistical
significance (13.2% vs 14.6%; P=.19). Among vaccine
recipients, 285 (73%) of all febrile illnesses were severe febrile illnesses
and 240 (61%) were febrile upper respiratory tract illnesses. For placebo
recipients, 173 (81%) of febrile illnesses were severe and 154 (72%) were
febrile upper respiratory tract illnesses.

During the peak outbreak periods, vaccination reduced all outcomes in
each prespecified illness category (Table
2). We observed a 10.0% to 23.6% reduction in the rates of illnesses
(P=.10 for febrile illnesses;
P≤.002 for all others), a 22.9% to 27.3% reduction in total rates
of days ill (P<.001 for all), a 13.1% to 28.4%
reduction in work-loss days, (P=.07 for febrile illnesses; P≤.01 for all others), and a 14.7% to 40.9% reduction
in days with at least 1 health care provider visit (P=.06
for febrile illnesses; P<.001 for all others).
Vaccination also led to reductions of 42.9% to 47.0% in the numbers of days
subjects took prescription antibiotics (P<.001)
and reductions of 23.3% to 28.0% in the numbers of days subjects took over-the-counter
medications (P<.001) Findings for the total outbreak
period were similar (Table 3).

COMMENT

In this study, intranasal trivalent LAIV vaccine was safe and well tolerated.
Although it did not significantly reduce the proportion of persons experiencing
at least 1 febrile illness, LAIV vaccine did significantly reduce the numbers
of severe febrile illnesses and febrile upper respiratory tract illnesses
among healthy, working adults. It also led to fewer numbers of days ill and
lower rates of work absenteeism, health care provider visits, and use of prescription
antibiotics and nonprescription medications.

Because these benefits
were observed during a season in which the predominant circulating influenza
virus strain, A/Sydney/05/97 (H3N2), was not well matched to the A(H3N2) strain
contained in the vaccine, the findings suggest that LAIV provided cross-protection
against the variant strain. During years with a better match between circulating
viruses and vaccine strains, the effectiveness of trivalent LAIV might be
even greater, although this has not been studied in adults. Cross-protection
against the A/Sydney/05/97 (H3N2) variant during the 1997-1998 season was
also demonstrated in a trial among children who received the intranasal LAIV
vaccine.23,24 Our trial did not
compare LAIV vaccine with trivalent inactivated vaccine, and it is not known
how the degree of cross-protection by LAIV against the A/Sydney/05/97 (H3N2)
variant might compare with that afforded by trivalent inactivated influenza
virus vaccine. However, several reports suggest that protection afforded by
the trivalent inactivated influenza vaccine may have been poor during the
1997-1998 season.21,25 Definitive
information regarding the relative degree of cross-protection afforded by
LAIV compared with inactivated vaccine, however, can be obtained only by directly
comparing these vaccines in a clinical trial.

One possible mechanism
for enhanced cross-protection might relate to the superior mucosal IgA and/or
T-cell–mediated immune response induced by the LAIV vaccine.9,12,13 Cytotoxic T cells
may be cross-reactive against different subtypes of influenza A viruses because
of their recognition of internal viral antigens expressed on the surfaces
of infected cells that are shared among influenza A viruses, despite antigenic
differences between the viral hemagglutinin molecules. The LAIV vaccine also
may induce the production of more broadly cross-reactive humoral antibodies.23

Immunization with inactivated influenza
virus vaccine can bring substantial health and economic benefits to healthy,
working adults during years with a good vaccine-circulating virus strain match.5,26- 31
Our results confirm that the prevention of influenza in working populations
reduces not only the burden of illness but also absenteeism and health care
resource use. Consistent with national prescribing trends,32,33
30% of placebo recipients in our study who reported 1 or more febrile upper
respiratory tract illnesses used prescription antibiotics (data not shown),
despite the minimal benefits these medications have for most upper respiratory
tract illnesses. The LAIV vaccine substantially reduced antibiotic use in
our study. The prevention of influenza through vaccination may reduce unnecessary
antibiotic use and thereby help control the emergence of antimicrobial resistance.

In our trial, recipients of the LAIV vaccine were more likely
than placebo recipients to report runny nose and sore throat during the week
following vaccination. These symptoms usually lasted only 1 or 2 days and
did not result in increased use of antibiotics, analgesics/antipyretics, or
antihistamines/decongestants/antitussives. The 2 groups experienced equivalent
rates of systemic symptoms, such as fever, headache, and muscle aches. Furthermore,
there were no serious adverse events attributed to receipt of either vaccine
or placebo in this study. Other studies have also demonstrated that bivalent
and trivalent formulations of the vaccine may be associated with increases
in mild upper respiratory tract symptoms but few, if any, other adverse effects.17,18 Together, these studies confirm that
LAIV vaccine is generally safe and well tolerated.

We used self-reported
illness to evaluate vaccine effectiveness in this study. Self-reported respiratory
tract illness can be highly reliable and valid compared with physician diagnoses.34 Our illness definitions were selected to be highly
sensitive and reflect findings that might be observed in daily clinical practice.
Because our illness definitions did not have the level of specificity that
might be obtained with laboratory confirmation of illness, our sample size
was adjusted accordingly. However, given the event rates we observed in our
study, our results suggest that the category of all febrile illnesses lacked
sufficient specificity for us to demonstrate a significant difference in the
proportion of participants experiencing illnesses. The illness definitions
that incorporated a greater degree of severity or that required the presence
of upper respiratory tract symptoms appeared to have greater specificity in
our study.

Only persons for whom we had follow-up data were included
in our analyses. For those lost to follow-up, we may have failed to capture
important outcome information. However, the rates of nonresponse were low
and equal in both groups, suggesting that the safety and effectiveness evaluations
were unbiased.

In conclusion, influenza is a common cause of illness,
absenteeism, and increased health care use in employed populations. Intranasally
administered trivalent LAIV vaccine safely and effectively reduced these manifestations
of influenza among healthy, working adults during a year in which a drifted
influenza A virus predominated. These findings have potential implications
for workers, their employers, and their health care providers.

Financial Disclosure: Dr Nichol has received research funding from Aviron, Pasteur-Merieux Connaught, Lyon, France, and Merck [[amp]] Co, West Point, Pa; Dr Gorse has received research funding from Aviron and VaxGen Inc, Brisbane, Calif; Dr Belshe has received research funding from Aviron and Wyeth-Lederle Vaccines and Pediatrics, St Davids, Pa; Drs Belshe and Wittes are paid consultants for Aviron; Dr Jackson has received research grants and honoraria from Aviron, Pasteur-Merieux Connaught, and Merck [[amp]] Co; and Dr Glezen has received vaccine from Aviron for a study funded by the National Institutes of Health.

Funding/Support: This study was sponsored by Aviron as part of the Collaborative Research and Development Agreement (CRADA) with the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md, and a licensing agreement with the University of Michigan, Ann Arbor. Aviron, Mountain View, Calif, sponsored the study and contracted with Parexel International to manage the conduct of the trial. Data analysis was planned and approved by the analysis committee, chaired by Dr Nichol, and was submitted to the US Food and Drug Administration before unblinding occurred. Dr Belshe monitored vaccine safety. The manuscript was prepared by the authors listed and reviewed by Aviron.

Acknowledgments: We thank the site clinical coordinators and Parexel International for their efforts on this study. We are also grateful to the following people from Aviron: Nick Bulley, clinical research associate; Annette Marcantonio, clinical research associate; Rebecca Redman, MD, medical monitor; and Jennifer A. L. Smith, PhD, statistician.

Batey D. A case study of influenza vaccine and its impact on absenteeism in
the work place: a randomized clinical trial at Exxon Company, USA. Presented at: Work Group Meeting on Improving the Performance of
Influenza and Pneumococcal Vaccines in Older Adults; November 14-15, 1995;
Washington, DC.

Figures

Figure 1. Trial Profile

During the days 0-28 safety phase of the trial, 3 participants (2
in vaccine group [0.07%] and 1 in placebo group [0.07%]) withdrew because
of adverse events. The 2 events among vaccine recipients were a hospitalization
for Crohn disease and an accidental drowning complicated by acute alcohol
intoxication. The event in a placebo recipient was related to psychiatric
illness not requiring hospitalization. None of these events was judged to
be related to receipt of the study treatment by the blinded study investigators.
An additional 15 participants (10 in vaccine group [0.3%] and 5 in placebo
group [0.3%]) either withdrew voluntarily or were noncompliant. Sixty-nine
vaccine recipients (2.3%) and 31 placebo recipients (2.0%) were lost to follow-up
and 2 others (1 in each group) cited other reasons for not providing the day
28 safety data. During the clinical effectiveness phase of the trial, participants
who did not return the symptom cards were considered lost to follow-up. LAIV
indicates live attenuated influenza virus.

Figure 2. Proportion of Study Participants
Reporting 1 or More Days of Symptoms During the 7 Days Following Vaccination

Asterisks indicate symptoms for which the rate among vaccine recipients
was significantly higher than among placebo recipients, with the upper limits
of the 95% confidence intervals for the differences including or exceeding
10% (see "Methods" section of text). The rates of the other symptoms were
equivalent between the groups. Fever was defined as an oral temperature of
more than 37.8°C.

Figure 3. Weekly Influenza Surveillance for
the 1997-1998 Influenza Season

Shown on the y-1 axis, with the bars, are the numbers of positive
influenza type A isolates reported to the Centers for Disease Control and
Prevention, Atlanta, Ga, by the World Health Organization collaborating laboratories
in the United States (adapted from reference 22). Shown on the y-2 axis, with
the line, are the numbers of positive influenza A isolates reported by the
study site laboratories. Fewer than 1% of all influenza isolates during the
1997-1998 season were influenza type B isolates and were therefore omitted
from the graph.

Batey D. A case study of influenza vaccine and its impact on absenteeism in
the work place: a randomized clinical trial at Exxon Company, USA. Presented at: Work Group Meeting on Improving the Performance of
Influenza and Pneumococcal Vaccines in Older Adults; November 14-15, 1995;
Washington, DC.

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